Extensive research on the chemotherapy of cancers has heretofore been conducted, with the chemotherapy of cancers commenced in the latter half of the 1940's for the control of nucleic acid metabolism. As antimetabolites to nucleic acids, 6-mercaptopurine was synthesized first, followed by the discovery of 5-fluorouracil.
5-fluorouracil was synthesized by Duschinsky in 1957 and found to have anti-cancer activity by Heidelberger et al. The compound has a wide anti-cancer spectrum range, produces outstanding effects especially on adenocarcinomas and is therefore one of the anti-cancer agents which are most widely used for clinical purposes. Since 5-fluorouracil is typical of antagonists to nucleic acid metabolism, intensive research is still continued on compounds having 5-fluorouracil as the basic skeleton.
In recent years, various excellent anti-cancer compositions have been introduced into use for the chemotherapy of malignant cancers with progressively improved results. Chemotherapeutic effects so far achieved nevertheless still remain temporary and are not always satisfactory in completely inhibiting the proliferation of cancerous tissues and enabling patients to survive a long period of time. The anti-cancer compositions frequently used for clinical purposes at present are predominantly those consisting essentially of a 5-fluorouracil, and various 5-fluorouracils will be developed in the future. However, anti-cancer compositions comprising a compound having a 5-fluorouracil as its skeleton and serving as the active component thereof have both merits and demerits. For example, 5-fluorouracil, although highly effective, has high toxicity and marked side effects. Accordingly, when administered, the compound produces a therapeutic effect and, at the same time, inevitably gives side effects. Further 1-(2-tetrahydrofuryl)-5-fluorouracil, which has relatively lower toxicity and reduces side effects, is said to be slightly inferior in its anti-cancer effect. In view of these situations, it has been expected to develop more advantageous 5-fluorouracils.
On the other hand, research has been conducted to provide increased anti-cancer efficacies by improving the method or mode of administering anti-cancer compositions which are conventionally used. For example, attempts have been made to use a known anti-cancer agent conjointly with another drug with or without anti-cancer activity to thereby achieve an increased therapeutic efficacy with reduced side effects. The known compositions of this type, nevertheless, are not fully effective for the chemotherapy of malignant cancers.
Compounds containing 5-fluorouracil as the skeleton thereof are thought to exhibit an anti-cancer effect when converted to 5-fluorouracil in the living body. It appears that they generally fail to give a high anti-cancer effect because the resulting 5-fluorouracil is promptly metabolized and thereby inactivated. Accordingly it is desired that the 5-fluorouracil in the living body be prevented from inactivation by some expedient, preferably in such a manner that the 5-fluorouracil present in the cancer tissues will remain active, whereas the 5-fluorouracil present in the normal tissues can be inactivated.
We have made extensive investigations for the development of anti-cancer compositions and have found that when uracil, which has no anti-cancer effect, was admixed with a 5-fluorouracil in an amount of 0.02 to 10 moles per mole of the latter, uracil enhanced the anti-cancer effect of the 5-fluorouracil, enabling the composition to achieve a remarkably increased therapeutic index (LD.sub.50 /ED.sub.50). Based on this finding, we filed patent applications (including Japanese Patent Applications No. 39341/1977 and No. 14676/1978, as well as U.S. Ser. Nos. 891,343 and 15,161).
With the above composition, a further increase in the proportion of uracil relative to the 5-fluorouracil results in a large dose, which is difficult to administer both physically and physiologically. Furthermore use of an increased proportion of uracil leads to a reduced LD.sub.50 and higher toxicity. For these reasons, it appeared favorable with filing e.g., U.S. Ser. No. 891,343, to limit the amount of uracil to 10 moles per mole of the 5-fluorouracil.
However, our experiments conducted with the use of compositions containing larger proportions of uracil have revealed that these compositions achieve much higher anti-cancer activity than when no more than 10 moles of uracil is used per mole of the 5-fluorouracil despite the decrease in the proportion of the 5-fluorouracil, thus making it possible to give such compositions at a reduced dose. When given to animals for toxicity tests in which the animals were checked for changes in body weight, the compositions were found to have reduced overall toxicity due to the decrease in the proportion of 5-fluorouracil.
Such results are totally inconceivably from conventional anti-cancer compositions since generally there is no anti-cancer agent that would act uniquely to cancer cells only; if effective on cancer, the usual anti-cancer compositions also invariably have side effects, which can be mitigated at a reduced dose, but a reduced efficacy will then result.